Bioerodible sustained release drug delivery systems

ABSTRACT

The present invention relates to sustained release drug delivery systems, medical devices incorporating said systems, and methods of use and manufacture thereof. The inventive systems feature bioerodible drug delivery devices that include biocompatible solid and biocompatible fluid compositions to achieve desired sustained release drug delivery.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/877,761, filed on Jun. 25, 2004, now U.S. Pat. No. 8,815,284, whichclaims the benefit of U.S. provisional application 60/483,316, filedJun. 26, 2003, U.S. provisional application 60/501,947, filed Sep. 11,2003, and U.S. provisional application 60/575,307, filed May 28, 2004,the specifications of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

Numerous techniques and systems have been developed to enhance drugdelivery. A principal objective is to provide the sustained release of adrug under conditions that allow sufficient control over the drug'sdelivery rate. Some systems employ a polymer drug delivery device insearch of such control, while others achieve sustained release bytemporarily altering the chemical properties of the agent or packagingthe agent with excipients or other agents. Nevertheless, systems areneeded that allow for improved control of drug delivery.

SUMMARY OF THE INVENTION

The present invention relates to sustained release drug delivery systemsfeaturing polymer drug delivery devices that include biocompatible fluidand biocompatible solid core components, where the biocompatible solidis less soluble in physiological fluid than in the biocompatible fluid.The systems allow desired sustained release drug delivery. The inventionalso contemplates medical devices employing such systems, and methods ofuse thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the release of bovine serum albumin (“BSA”) from asemi-solid gel formed from BSA and PLGA-PEG in a sealed silicone cupwith a small hole into 0.1 M phosphate buffer, pH 7.4, as monitored byHPLC.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a polymer drug delivery system (“polymer system”)comprising an inner core or reservoir that contains a therapeuticallyeffective amount of an agent, a first coating layer that is impermeable,negligibly or partially permeable to the agent and, optionally, a secondcoating layer that is permeable or semi-permeable to the agent.Additional layers may also optionally be used.

The inner core has biocompatible fluid and biocompatible solidcomponents, where the biocompatible solid is less soluble inphysiological fluid than in the biocompatible fluid. The biocompatiblefluid may be hydrophilic, hydrophobic or amphiphilic; and may bepolymeric or nonpolymeric. Such fluid may also be a biocompatible oil(such as sesame oil, miglyol, or the like). In certain embodiments, abiocompatible solid (e.g., a bioerodible polymer) is dissolved,suspended, or dispersed in the biocompatible fluid (to form a“biocompatible core component”). In certain embodiments, at least oneagent is also dispersed, suspended, or dissolved in the biocompatiblecore component. In certain embodiments, an agent is dissolved in thebiocompatible fluid. In certain embodiments, the biocompatible fluid isa liquid agent that, when combined with a biocompatible solid, is in aform suitable for injection.

In certain embodiments, the inner core has biocompatible fluid andbiocompatible solid components, wherein the biocompatible fluidcomponent is a liquid drug or includes a liquid with a drug dissolvedtherein, and the biocompatible solid component is dissolved, suspended,or dispersed in the liquid drug to form a biocompatible core component.Other drugs or agents may, but need not, be dispersed, suspended, ordissolved in the biocompatible core component.

The first coating layer surrounds the inner core, is an impermeable,negligibly or partially permeable polymer, and may feature one or morediffusion ports or pores (“pores”) that further allow the drug todiffuse from the core out of the system. The rate of drug release fromsuch systems may be controlled by the permeability of the agent in thecore, the solubility of the agent in the biocompatible core component,the thermodynamic activity of the agent in the biocompatible corecomponent, the potential gradient of the agent from the core tosurrounding physiological fluid, the size of the diffusion pore(s),and/or the permeability of the first or additional coating layer(s). Incertain embodiments, the coating layer(s) is bioerodible, while in otherembodiments it is non-bioerodible.

U.S. Pat. Nos. 5,378,475, 5,773,019, 5,902,598, 6,001,386, and6,375,972, as well as co-pending U.S. patent application Ser. No.10/428,214 and 60/501,947 disclose various embodiments of sustainedrelease drug delivery systems with one or more polymer coating layers.By way of illustration and not limitation, such devices may be usefullyemployed with the systems described herein, and the entire disclosuresof those references are incorporated herein by reference.

In preferred embodiments, the first coating layer includes at least onepolymer (and may, optionally, include more than one polymer), and ispreferably bioerodible, but may alternatively be non-bioerodible. Thefirst coating layer covers at least part but preferably not all of thesurface of the inner core, leaving at least one diffusion pore throughwhich the agent can pass from the inner core. In certain embodiments,particularly where impermeable, the membrane may have one or more pores.If a second layer is used, it may partially cover or cover essentiallyall of the first coating layer and inner core, and its permeability tothe agent permits the agent to diffuse into the surrounding fluid.

A variety of polymers may be suitable to form the coating layer(s) ofthe present invention. Preferable polymers are largely insoluble inphysiological fluids. Suitable polymers may include naturally occurringor synthetic polymers. Certain exemplary polymers include, but are notlimited to, polyvinyl acetate, cross-linked polyvinyl alcohol,cross-linked polyvinyl butyrate, ethylene ethylacrylate copolymer,polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals,plasticized ethylene vinylacetate copolymer, polyvinyl alcohol, ethylenevinylchloride copolymer, polyvinyl esters, polyvinylbutyrate,polyvinylformal, polyamides, polymethylmethacrylate,polybutylmethacrylate, plasticized polyvinyl chloride, plasticizednylon, plasticized soft nylon, plasticized polyethylene terephthalate,natural rubber, polyisoprene, polyisobutylene, polybutadiene,polyethylene, polytetrafluoroethylene, polyvinylidene chloride,polyacrylonitrile, cross-linked polyvinylpyrrolidone,polytrifluorochloroethylene chlorinated polyethylene,poly(1,4-isopropylidene dipehenylene carbonate), vinylidene chloride,acrylonitrile copolymer, vinyl-chloride-diethyl fumerale copolymer,silicone rubbers, medical grade polydimethylsiloxanes,ethylene-propylene rubber, silicone-carbonate copolymers, vinylidenechloride-vinyl chloride copolymer, vinyl chloride-acrylonitrilecopolymer, vinylidene chloride-acrylonitride copolymer, etc.

The biocompatible core component includes at least one biocompatiblesolid (e.g., a bioerodible polymer) that is at least partiallydissolved, suspended, or dispersed in a biocompatible polymeric ornonpolymeric fluid or a biocompatible oil. Further, the biocompatiblesolid is more soluble in the biocompatible fluid or oil than inimmediately surrounding physiological fluid such that, when the deviceis placed in contact with physiological fluid, the biocompatible corecomponent precipitates or undergoes a phase transition. The inner coremay be delivered as a gel. It may preferably be delivered as aparticulate or a liquid that converts to a gel upon contact with wateror physiological fluid. In some embodiments, the biocompatible (e.g.,nonpolymeric) fluid may include a drug in free base form.

In certain embodiments, the biocompatible fluid of the biocompatiblecore component is hydrophilic (e.g., PEG, cremophor, polypropyleneglycol, glycerol monooleate, and the like), hydrophobic, or amphiphilic.In certain embodiments, said fluid may be a monomer, polymer or amixture of the same. If used, the biocompatible oil may be sesame oil,miglyol, or the like.

In certain embodiments, injectable liquids may be used that, uponinjection, undergo a phase transition and are transformed in situ intogel delivery vehicles. In certain embodiments, at least one polymer inthe inner core may convert from a drug-containing liquid phase to adrug-infused gel phase upon exposure to a physiological fluid.Technologies based on in situ gelling compositions are described in U.S.Pat. Nos. 4,938,763, 5,077,049, 5,278,202, 5,324,519, and 5,780,044, allof which may be adapted to the present invention, and the disclosure ofeach is incorporated herein by reference.

In certain embodiments, the agent may be covalently linked to apolyoxyethylene ether, wherein the covalent bonds are cleavable in vivoso as to release the agent. In certain embodiments, the agent isreleased in a sustained manner. Methods shown for forming and applyingconjugate prodrugs (e.g., PEG—drug conjugates) are shown in U.S. Pat.No. 5,681,964 and in U.S. Provisional Application No. 60/539,306, thespecifications of which are incorporated by reference in their entiretyherein.

In certain embodiments, the agent is a pegylated prodrug of anotheragent.

In certain embodiments the agent may be included in compounds havingstructure 1 below:A(-L-)_(m)S_(n)  1wherein A is a residue of a pharmaceutically active agent A′, Lrepresents a covalent bond or a linker moiety, and S is apolyoxyethylene ether group having the formula —(OCH₂CH₂)_(p)OR, where pis 2-12 and R is a C₁-C₄ alkyl group. The biocompatible fluid maycomprise a mixture of compounds having a range of values of p; but inpreferred embodiments p has a single value and the composition comprisesonly one compound of structure 1. The bond or linker L is cleavable invivo so as to release the active agent A′. The agent A′ will typicallyfeature one or more functional groups to which linkers L can be readilyattached. Examples of such functional groups include but are not limitedto —CO₂H, —CONH₂, —CHO, ═O, —OH, —NH₂, and —SH groups.

Examples of bonds and linkages which are cleavable in vivo, either byhydrolysis or by enzyme catalysis, include but are not limited toesters, amides, carbamates, carbonates, orthoesters, cyclic ketals,thioesters, thioamides, thiocarbamates, thiocarbonates, xanthates,disulfides, and phosphate esters. Ester linkages, carbonate linkers,and/or amino acid linker moieties are preferred. Enzymatically cleavablelinkers for polyoxyethylene derivatives have been described, forexample, in U.S. Pat. No. 6,127,355, Ulbrich et al., Makromol. Chem.1986; 187:1131-1144, Conover et al., and Anti-Cancer Drug Design 1999;14:499-506, and in many of the references cited therein, and the use ofsuch linkers is specifically contemplated. Ester linkages may also beused (see R. Bronaugh et al., Percutaneous Absorption 3rd Ed., p. 58-63,R. L. Bronaugh and H. I. Maibach, eds., Marcel Dekker, New York, 1999).

The values of m and n will typically range from 1 to 4, although largervalues are within the scope of the invention. Typically, the linker isdivalent and m and n will have the same value, but multiple links to asingle moiety S, as for example in a ketal or orthoester linkage, may beemployed. Alternatively, multiple moieties S may be appended via asingle linker L, for example by esterification of the agent A with amoiety such as —C(═O)CH[(OCH₂CH₂)_(p)OR]₂ or —P(═O)[(OCH₂CH₂)_(p)OR]₂.Where m>1 and/or n>1, each incidence of L and S may be the same ordifferent.

The residue represented by A may be derived from any agent, includingbut not limited to steroids (preferably corticosteroids), retinoids,NSAIDs, vitamin D3 and vitamin D3 analogs, antibiotics, and antiviralagents. Other suitable agents include enzymes, peptides and other largemolecules. In certain embodiments of this invention, all-trans retinoicacid is excluded from the residues represented by A, while in otherembodiments retinoids are excluded from the residues represented by A.

Suitable steroids include but are not limited to androgenic andestrogenic steroid hormones, androgen receptor antagonists and5-α-reductase inhibitors, and corticosteroids. Specific examples includebut are not limited to alclometasone, clobetasol, fluocinolone,fluocortolone, diflucortolone, fluticasone, halcinonide, mometasone,prednisone, prednisolone, methylprednisolone, triamcinolone,betamethasone, and dexamethasone, and various esters and acetonidesthereof.

Suitable retinoids include but are not limited to retinol, retinal,isotretinoin, acitretin, adapalene, tazarotene, and bexarotene.

Suitable NSAIDs include but are not limited to naproxen, suprofen,ketoprofen, ibuprofen, flurbiprofen, diclofenac, indomethacin,celecoxib, and rofecoxib.

Suitable vitamin D3 analogues include but are not limited todoxercalciferol, seocalcitol, calcipotriene, tacalcitol, calcitriol,ergocalciferol, and calcifediol.

Suitable antiviral agents include but are not limited to trifluridine,cidofovir, acyclovir, penciclovir, famciclovir, valcyclovir,gancyclovir, and docosanol. Suitable antibacterial agents include butare not limited to metronidazole, clindamycin, erythromycin, vancomycin,ciprofloxacin, ofloxacin, lomefloxacin, bacitracin, neomycin, mupirocin,and polymyxin B. The antiviral and antibacterial prodrugs of theinvention may be used to treat appropriately responsive systemicinfections.

The linker L is cleavable in vivo, meaning that the compound of theinvention is hydrolyzed or otherwise cleaved, with or without enzymaticcatalysis, so as to generate in situ the active agent.

Examples of suitable linkers include, but are not limited to, —CH₂O—,—OCH₂O—, —C(═O)—O—, —OC(═O)—O—, —C(═O)—(CH₂)₁₋₄—O—, and—C(═O)—(CH₂)₁₋₄—, —C(═O)—NH—, and —C(═S)—NH—. Descriptions of suitablelinkers may be found in Prodrugs: Topical and Ocular Drug Delivery,1992, K. B. Sloan (Ed.), Drugs and the Pharmaceutical Sciences, Vol 53(Marcel Dekker). It will be appreciated that the rate of cleavage willvary depending on the precise structures of the active agent and thepolyoxyethylene ether, and on the nature of the linker or bond L and thepoint(s) of attachment. The efficiency of prodrug cleavage of linkersfor any specific embodiment can be readily determined by those of skillin the art; for a review of methods see A. Stichcomb, 2003, Pharm Res.20:1113-1118.

The linker or bond L may be attached to any suitable heteroatom presentin the topically active agent that carries an exchangeable hydrogen,such as —OH, SH, NH₂, and COOH groups. By way of example, the freehydroxyl group of triamcinolone acetonide may be acylated with themoiety —C(═O)(OCH₂CH₂)_(p)OR.

In one embodiment, the active agent comprises a carboxylic acid group,and the carboxylic acid group is esterified with a polyoxyethylene etherof formula HO(CH₂CH₂O)_(p)R. Examples include but are not limited tostructures I, II, and III shown below:

In an alternative embodiment, the active agent comprises a hydroxylgroup, and the hydroxyl group is acylated with a polyoxyethylene ethercarbonyl moiety of formula —CO(OCH₂CH₂)_(p)OR. Examples include but arenot limited to structures IV and V shown below:

In certain embodiments, the biocompatible fluid includes a prodrugcomprising a pharmaceutical compound linked to a polyoxyethylene ethermoiety of the formula: —(OCH₂CH₂)_(p)OR, wherein p=2-12 and R is a C₁-C₄alkyl group. In certain embodiments, n is an integer from 2 to 6inclusive. The identities of the group R may be methyl, ethyl, or anyother organic moiety.

In certain embodiments, the use of prodrug linkages in connection withan agent may improve the solubility of an agent in water or in polymer.For example, the use of a pegylated prodrug may improve the solubilityof an agent in the biocompatible fluid, and thereby improve theinjectability of the invention. The use of prodrug linkages may alsolower the melting point of a solid agent, or increase the solubility ofan agent in physiological fluids, thereby improving the injectability ofthe agent.

The agent may be dissolved, dispersed or suspended in the biocompatiblecore, whereupon it may leach out of the core and into surrounding fluid.In certain embodiments, the agent may rapidly escape from an injectionmixture after injection into a physiological system.

In certain embodiments, the biocompatible solid component may be, forexample but without limitation, poly(lactic co-glycolic) acid (PLGA).

In certain embodiments the inner core is a viscous paste containing atleast 10% agent, or preferably over 50% agent or, more preferably, over75% agent.

In certain embodiments, the polymer system is injected or inserted intoa physiological system (e.g., a patient). Upon injection or insertion,the delivery system will contact water or other immediately surroundingphysiological fluid that will enter the polymer system and contact theinner core. In certain embodiments, the core materials may be selectedso as to create a matrix that reduces (and thereby allows control of)the rate of release of the agent from the delivery system.

In preferred embodiments, the agent's rate of release from the system islimited primarily by the permeability or solubility of the agent in thematrix. However, the release rate may be controlled by various otherproperties or factors. For example, but without limitation, the releaserate may be controlled by the size of the diffusion pore(s), thepermeability of the second layer of the polymer system, the physicalproperties of the core (e.g., the permeability or solubility of an agentin the biocompatible solid as opposed to the permeability or solubilityof the agent in the biocompatible fluid of the biocompatible corecomponent), the dissolution rate of the core or components of the core,or the solubility of the agent in the physiological fluid immediatelysurrounding the polymer system.

In certain embodiments, the rate of release of the agent may be limitedprimarily by any of the foregoing properties. For example, in certainembodiments, the rate of release of the agent may be controlled, or evenlimited primarily by, the size of the diffusion pore(s). Depending onthe desired delivery rate of the agent, the first layer may coat only asmall portion of the surface area of the inner core for faster releaserates of the agent (i.e., the diffusion pore(s) is relatively large), ormay coat large portions of the surface area of the inner core for slowerrelease rates of the agent (i.e., the diffusion pore(s) is relativelysmall).

For faster release rates, the first layer may coat up to about 10% ofthe surface area of the inner core. In certain embodiments,approximately 5-10% of the surface area of the inner core is coated withthe first layer for faster release rates.

Certain embodiments may achieve desirable sustained release if the firstlayer covers at least 25% of the surface area of the inner core,preferably at least 50% of the surface area, more preferably at least75%, or even greater than 85% or 95% of the surface area. In certainembodiments, particularly where the agent is readily soluble in both thepolymer core and the biological fluid, optimal sustained release may beachieved if the first layer covers at least 95% or 99% of the innercore. Thus, any portion of the surface area of the inner core, up to butnot including 100%, may be coated with a first coating layer to achievethe desired rate of release of the agent.

The first coating may be positioned anywhere on the inner core,including but not limited to the top, bottom or any side of the innercore. In addition, it could be on the top and a side, or the bottom anda side, or the top and the bottom, or on opposite sides or on anycombination of the top, bottom or sides.

The composition of the first coating layer is selected so as to allowthe above-described controlled release. The preferred composition of thefirst layer may vary depending on such factors as the active agent, thedesired rate of release of the agent and the mode of administration. Theidentity of the active agent is important because its molecular sizedetermines, at least in part, its rate of release into the second layer.

In certain embodiments, the release rate of the agent from the innercore may be reduced by the permeability of the second coating layer. Incertain embodiments, the second layer is freely permeable to the agent.In certain embodiments, the second layer is semi-permeable to the agent.In certain embodiments, the agent has a permeability coefficient in thesecond coating layer of less than about 1×10⁻¹⁰ cm/s. In otherembodiments the permeability coefficient in the second coating layer isgreater than 1×10⁻¹⁰ cm/s, or even greater than 1×10⁻⁷ cm/s. In certainembodiments the permeability coefficient is at least 1×10⁻⁵ cm/s, oreven at least 1×10⁻³ cm/s, or at least 1×10⁻² cm/s in the second layer.

In certain embodiments, the agent has a permeability coefficient in thefirst coating layer of less than about 1×10⁻¹⁰ cm/s. In otherembodiments the permeability coefficient in the first coating layer isgreater than 1×10⁻¹⁰ cm/s, or even greater than 1×10⁻⁷ cm/s. In certainembodiments the permeability coefficient is at least 1×10⁻⁵ cm/s, oreven at least 1×10⁻³ cm/s, or at least 1×10⁻² cm/s in the first coatinglayer.

In certain embodiments, the inner core undergoes a phase change (i.e.the biocompatible solid precipitates) and converts to a gel upon implantor insertion of the polymer system in a physiological system. The phasechange may reduce the rate of release of the agent from the inner core.For example, where at least part of the core is provided first as aliquid and converts to a gel, the gel phase of the polymer core may beless permeable to the agent than is the liquid phase of the polymer coreprior to the conversion to the gel. In certain embodiments, the polymercore in gel phase is at least 10% or even at least 25% less permeable tothe agent than is the liquid phase. In other embodiments, theprecipitated biocompatible solid is at least 50% or even at least 75%less permeable to the agent than is the biocompatible fluid alone.

In certain embodiments, interaction of the core with the physiologicalfluid may alter the solubility of the agent in the core, and therebyreduce the release rate of the agent. For example, the core may be atleast 10% or even at least 25% less solubilizing to the agent thanbefore interaction with physiological fluid; in other embodiments, wherea gel phase occurs, the gel phase is at least 50% or even at least 75%less solubilizing to the agent.

In certain embodiments, the biocompatible solid and/or biocompatiblefluid components of the core may dissolve when in contact withphysiological fluid. The rate at which such components dissolve mayimpact the rate of release of the agent. In certain embodiments, as thecore component(s) erode or dissolve, the rate of release of the agentmay increase. For example, in certain embodiments less than about 10% ofthe core component(s) may erode or dissolve over a period of about 6hours. This may increase the rate of release of the agent by less thanabout 10% over that time. In certain embodiments, the biocompatible corecomponent(s) may erode or dissolve more slowly (e.g. less than about 10%over a period of about 24 hours, or even over a period of multiple days,weeks, or even months). In certain embodiments, such erosion ordissolution may occur more rapidly (e.g. greater than about 10% over aperiod of about 6 hours, in certain embodiments even greater than 25%over a period of about 6 hours).

In certain embodiments, the solubility of the agent in the core impactsthe rate of release of the agent from the polymer system. In certainembodiments, the agent is soluble, moderately soluble, or even slightlysoluble or very slightly soluble in the core. The agent's release ratefrom the polymer core where an agent is soluble in the core exceeds therate of release where the agent is only slightly or very slightlysoluble in the polymer core.

In certain embodiments, the release rate of the agent from the innercore may be controlled by the ratio of the agent to the biocompatiblesolid component of the core (also referred to as the “drug loading”). Bychanging the drug loading, different release rate profiles can beobtained. Increasing the drug loading may increase the release rate. Fora slower release profile, drug loading may be less than 10%, andpreferably less than 5%. For a faster release profile, drug loading maybe more than 10%, and preferably more than 20%, or even greater than50%.

In certain embodiments, the agent may have low solubility in thephysiological fluid immediately surrounding the implanted/insertedpolymer system. In such embodiments, the rate of release of the agentfrom the polymer system may be controlled by the solubility of the agentin such surrounding fluid (i.e., the lower the solubility of the agentin the immediately surrounding fluid the lower its rate of release fromthe polymer system). In certain embodiments, the solubility of the agentin the surrounding physiological fluid is moderate or less.

In certain embodiments, the agent is a codrug, or a prodrug thereof,wherein the codrug or prodrug thereof is at least 5% less soluble in thesurrounding physiological fluid than are its constituent components. Insuch embodiments, the rate of release of the agent may be at least 5%less than the rate of release of the unlinked constituents from thepolymer system. In certain embodiments, the codrug or prodrug thereof isat least 10%, even at least 25%, at least 50%, or at least 75% lesssoluble in the surrounding fluid than are its unlinked constituents. Therate of release of the constituents may be reduced accordingly whenprovided in codrug (or prodrug thereof) form as compared to theirunlinked forms. In certain embodiments using a codrug, the codrugdisassociates upon contact with physiological fluid to generate andrelease one or more therapeutically active agents from the core.

Thus, the rate of release of the agent according to the invention may belimited primarily by any of the above properties or any other factor.For example, but without limitation, the release rate may be controlledby the size and/or location of the diffusion pore(s), the permeabilityor other properties of the first or a second layer in the polymersystem, the physical properties of the core (e.g., a gel after a phasetransition), the dissolution rate of one or more of the core components,the solubility of the agent within the core, the solubility of the agentin the physiological fluid immediately surrounding the polymer system,etc. In certain preferred embodiments, the release of the agent may belimited primarily by any one factor, such that the rate of release islower as a result of that one factor. In certain embodiments, the rateof release of the agent is at least 10% slower as a result of one factorthan as a result of any other factor. In certain embodiments, the rateof release of the agent is at least 25%, or even at least 50% or atleast 75% slower as a result of one factor than as a result of any otherfactor.

The foregoing factors are illustrative only. The skilled artisan willreadily appreciate that any other property of the inventive system maybe the limiting factor in the agent's release rate from the system.

In another aspect, the inventive system is provided in a drug deliverydevice capable of delivering one drug or even two or more synergisticdrugs over a prolonged period. In certain embodiments, the inventivesystem provides sustained release of a therapeutically effective amountof an agent to a patient in need thereof. In preferred embodiments, thedevice allows delivery of the compounds over a period of at least 3hours, preferably at least 12 hours, or even 1 day, at least 2 days, oreven at least 1 week, at least 1 month, or at least 1 year. In someembodiments, the inventive system may be deployed on a stent or otherdevice. Such devices include, but are not limited to surgical screws,prosthetic joints, artificial valves, plates, pacemakers, sutures, etc.

Definitions

The term “active” as used herein means biologically, therapeutically orpharmacologically active.

The term “agent” as used herein is synonymous with “at least one agent,”“compound,” or “at least one compound,” and means at least one drug orcodrug, or a prodrug thereof. In certain embodiments, the agent may beat least one low-solubility codrug, or a prodrug thereof. In certainembodiments the codrug, or prodrug thereof, is designed to have lowsolubility in either the core, the biological fluid or both. In certainembodiments, the agent may be a protein, peptide, or a pegylated agent.In still other embodiments, the term “agent” refers to a plurality ofdrugs, proteins, peptides, etc. In certain embodiments the agent may bein granular form. In certain embodiments, the agent may be combined witha pharmaceutically acceptable carrier. In certain embodiments, the agentis in liquid form.

An “effective amount” of an agent, with respect to methods of treatment,refers to an amount of the agent in a preparation which, whenadministered as part of a desired dosage regimen (to a mammal,preferably a human) alleviates a symptom, ameliorates a condition, orslows the onset of disease conditions according to clinically acceptablestandards for the disorder or condition to be treated or the cosmeticpurpose.

The term “ED₅₀” means the dose of a drug that produces 50% of itsmaximum response or effect.

The terms “granule,” “particle,” or “particulate” as used herein areused interchangeably and refer to any particle. In certain exemplaryembodiments, the particles have a diameter in the range of about 0.01 mmto about 3 mm, preferably in the range of about 0.1 mm to about 2 mm, oreven more preferably in the range of about 0.3 mm to about 1.5 mm.

As used herein, the term “EC₅₀” means the concentration of a drug thatproduces 50% of its maximum response or effect. The term “IC₅₀” meansthe dose of a drug that inhibits a biological activity by 50%.

The term “LD₅₀” means the dose of a drug that is lethal in 50% of testsubjects.

The term “therapeutic index” refers to the therapeutic index of a drugdefined as LD₅₀/ED₅₀.

A “patient” or “subject” to be treated by the inventive system refers toeither a human or non-human animal.

“Physiological conditions” describe the conditions inside an organism,i.e., in vivo. Physiological conditions include the acidic and basicenvironments of body cavities and organs, enzymatic cleavage,metabolism, and other biological processes, and preferably refer tophysiological conditions in a vertebrate, such as a mammal.

In general, “low solubility” means that the agent is only very slightlysoluble in a medium (e.g., aqueous solutions having pH in the range ofabout 5 to about 8, and in particular to physiologic solutions, such asblood, blood plasma, etc., other relevant mediums include gels and othermaterials in the polymer core). Some agents, e.g., low-solubilityagents, will have solubilities of less than about 1 mg/ml in the medium,less than about 100 μg/ml, preferably less than about 20 μg/ml, morepreferably less than about 15 μg/ml, and even more preferably less thanabout 10 μg/ml. Solubility in water is measured at a temperature of 25°C. as measured by the procedures set forth in the 1995 USP, unlessotherwise stated. According to the invention, compounds which aresoluble (greater than about 100 mg/ml), moderately soluble (about 100mg/ml to about 10 mg/ml), slightly soluble (about 10 mg/ml to about 1mg/ml), very slightly soluble (about 1 mg/ml to about 0.1 mg/ml) andpractically insoluble or insoluble compounds (less than about 0.1 mg/ml,preferably less than about 0.01 mg/ml) are contemplated.

As used herein, an agent's “Log P” refers to the logarithm of P(Partition Coefficient), where P is a measure of how the agentpartitions between octanol and water. P itself is a constant, defined asthe ratio of concentration of compound in aqueous phase to theconcentration of compound in octanol according to the following:Partition Coefficient,P=[Organic]/[Aqueous], where [ ]=concentrationLog P=log₁₀(Partition Coefficient)=log₁₀ P

A Log P value of 1 means that the concentration of the compound is tentimes greater in the organic phase than in the aqueous phase. Theincrease in a Log P value of 1 indicates a ten-fold increase in theconcentration of the compound in the organic phase as compared to theaqueous phase.

The term “residue” when applied to an agent means a part of an agentthat is substantially identical to the agent from which it is derived,with minor differences arising by virtue of having one or more atomsremoved to provide points of attachment for the linker(s) L. Typically,at least one functional group of the residue will be altered (relativeto the parent pharmaceutically active agent) to accommodate the covalentlinker. This will typically involve removal of an exchangeable hydrogenand/or a single heteroatom, leaving a free valence for attachment of thelinkage L. For instance, where the agent includes a carboxylatefunctional group, the residue of the agent formed by removal of ahydroxyl group may form an ester bond with a hydroxyl group on apolyoxyethylene ether residue, which itself is formed by removal of ahydrogen atom from a hydroxyl group from the polyoxyethylene ether. Inthis sense, the term “residue” as used herein is analogous to the senseof the word as it is used in peptide and protein chemistry to refer to aresidue of an amino acid in a peptide.

The terms “linker” and “linkage,” which are used interchangeably herein,refer to a direct bond or to a multivalent group of atoms incorporatingand connecting the functional groups of the active agent and apolyoxyethylene ether, which is metabolized under physiologicalconditions to release the active agent A′. In certain embodiments, thelinker is a substantially linear moiety having no more than 25 atoms,more preferably less than 10 atoms. Preferred linkers are ones which,upon release of the topically active agent, and when furthermetabolized, generate byproducts that are non-toxic and inert at theeffective dosing concentration. Direct bonds between the residue A andthe polyoxyethylene moiety S are particularly preferred.

The term “codrug” as used herein means a compound comprising a firstmolecule residue associated with a second molecule residue, wherein eachresidue, in its separate form (e.g., in the absence of the association),is an active agent or a prodrug of an active agent. In preferredembodiments, either one or both of the first and second moleculeresidues are small molecules. The association between said residues canbe either ionic or covalent and, in the case of covalent associations,either direct or indirect through a linker. The first molecule can bethe same or different from the second. Exemplary formulae for codrugscan be seen in formulae I, Ia, II, IIa, III, IIIa, and IV:A₁*(-L-A₂*)_(n)  (I)A₁*(-A₂*)_(n)  (Ia)A₁*-L-A₂*  (II)A₁*-A₂*  (IIa)A₂*-L-A₁*-L-A₂*  (III)A₂*-A₁*-A₂*  (IIIa)A₁*::A₂*  (IV)

wherein each of A₁*, A₂*, and L are defined as follows:

A₁* is a residue of a first biologically active compound, A₁;

A₂* is a residue of a second biologically active compound, A₂, which maybe the same as or different from A₁;

L is a linking group selected from a direct bond and a divalent organiclinking group; and

n is an integer having a value of from 1 to 4, preferably 1;

and :: is an ionic bond.

The term “prodrug” as used herein means a first residue associated witha second residue, wherein one of the residues is biologically active. Inpreferred embodiments, either one or both of the first and secondresidues are small molecules. In some embodiments, one of the residuesis not biologically active; in some embodiments the prodrug may bebiologically inactive in its prodrug form. The association between saidresidues is covalent and can be either direct or indirect through alinker. Prodrugs of biologically active compounds include esters, aswell as anhydrides, amides, and carbamates that are hydrolyzed inbiological fluids to produce the parent compounds. Those skilled in theart will realize that a “prodrug” is a moiety that is generally notpharmacologically active. However, when activated, typically in vivo byenzymatic or hydrolytic cleavage to convert the prodrug to an activebiological moiety, the administration of the prodrug to the individualwill have had the intended medical effect. Prodrugs are typically formedby chemical modification of a biologically active moiety. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, ed. H.Bundgaard, Elsevier, 1985.”

The term “physiological pH,” as used herein, refers to a pH that isabout 7.4 at the standard physiological temperature of 37.4° C. The term“non-physiological pH,” as used herein, refers to a pH that is less thanor greater than “physiological pH,” preferably between about 4 and 7.3,or greater than 7.5 and less than about 12. The term “neutral pH,” asused herein, refers to a pH of about 7. In preferred embodiments,physiological pH refers to pH 7.4, and non-physiological pH refers to pHbetween about 6 and 7. The term “acidic pH” refers to a pH that is belowpH 7, preferably below about pH 6, or even below about pH 4.

The term “bioerodible” is synonymous with “biodegradable” and isart-recognized. It includes polymers, compositions and formulations,such as those described herein, that degrade during use. Biodegradablepolymers typically differ from non-biodegradable polymers in that theformer may be degraded during use. In certain embodiments, such useinvolves in vivo use, such as in vivo therapy, and in other certainembodiments, such use involves in vitro use. In general, degradationattributable to biodegradability involves the degradation of abiodegradable polymer into its component subunits, or digestion, e.g.,by a biochemical process, of the polymer into smaller, non-polymericsubunits. In certain embodiments, biodegradation may occur by enzymaticmediation, degradation in the presence of water and/or other chemicalspecies in the body, or both.

The terms “biocompatible” and “biocompatibility” when used herein areart-recognized and mean that the referent is neither itself toxic to ahost (e.g., an animal or human), nor degrades (if it degrades) at a ratethat produces byproducts (e.g., monomeric or oligomeric subunits orother byproducts) at toxic concentrations, causes inflammation orirritation, or induces an immune reaction, in the host. It is notnecessary that any subject composition have a purity of 100% to bedeemed biocompatible. Hence, a subject composition may comprise 99%,98%, 97%, 96%, 95%, 90% 85%, 80%, 75% or even less of biocompatibleagents, e.g., including polymers and other materials and excipientsdescribed herein, and still be biocompatible.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filter, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a subject drug from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withother ingredients of the formulation and not injurious to the patient.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include (1) sugars, such as lactose, glucose andsucrose; (2) starches, such as corn starch and potato starch; (3)cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5)malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter andsuppository waxes; (9) oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10)glycols, such as propylene glycol; (11) polyols, such as glycerin,sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyloleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19)ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations.

The phrase “protecting group” or “protective group” as used herein meansa temporary substituent that protects a potentially reactive functionalgroup from undesired chemical transformations. Examples of suchprotecting groups include esters of carboxylic acids, silyl ethers ofalcohols, and acetals and ketals of aldehydes and ketones, respectively.The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2^(nd) ed.;Wiley: New York, 1991).

The term “residue” refers to that part of a compound that remains afterthe compound is linked, either directly to another compound by a directbond or to a divalent linking moiety. For instance, where a residue A₁comprises a carboxylic acid group that forms a linkage to a secondresidue A₁ through an amino group to form the compound A₁-A₁, includingan amide linkage, the first residue A₁ is the residue of the parentcompound that includes all of the parent except for the —OH that formspart of the amide group, while the other includes all of the parentexcept an H— from the amino group. A person having skill in the art willrecognize that this is analogous to “residues” of amino acids inpolypeptides and proteins, or to “residues” of ribonucleotides anddeoxyribonucleotides in RNA and DNA, respectively.

According to the present invention, the phrase “limited primarily by”refers to the factor(s) associated with the rate-determining step in therelease rate of an agent from the inventive system. For example, butwithout limitation, an agent's release rate is limited primarily by therate of the agent's dissolution in the polymer where said rate ofdissolution is the rate determining step in the release of the agent(e.g., said dissolution is slower than the rate of dispersion of theagent in the surrounding physiological fluid). Similarly, where the rateof release (e.g., the rate-determining step) is a result of theproperties of the matrix (e.g., molecular weight, permeability in gelstate to passage of the agent, size of the diffusion pore), the rate ofrelease is also said to be “limited primarily by” such properties, suchmatrix, etc.

Exemplary Embodiments

In one embodiment, poly(lactic-co-glycolic acid) (PLGA) is dissolved inpolyethylene glycol (PEG); the solution is kept in a 37° C. water bath.Equal amount of the PLGA-PEG solution and bovine albumin are mixed andform a semi-solid gel. This gel is filled into a silicone cup (1.5 mmID) with a small hole in the bottom, and the top of the cup is thensealed with silicone adhesive. The hole in the bottom can be left openor coated with a polymer membrane to control the release. The finishedassembly (silicone cup filled with Albumin-PGA-PEG gel) is placed in 0.1m phosphate buffer (pH 7.4) at 37° C., and the release amount of albuminis analyzed using HPLC (FIG. 1).

The foregoing embodiment is presented for illustrative purposes only,and is not intended to be limiting. The person skilled in the art willrecognize that additional embodiments according to the invention arecontemplated as being within the scope of the foregoing genericdisclosure, and no disclaimer is in any way intended by the foregoing,non-limiting examples.

All patents, publications, and references cited in the foregoingdisclosure are expressly incorporated herein by reference.

The invention claimed is:
 1. A drug delivery system comprising: an innercore, comprising (i) a biocompatible fluid component, (ii) abiocompatible solid component, wherein said biocompatible solidcomponent comprises a bioerodible polymer, and said biocompatible solidcomponent is dissolved, suspended, or dispersed in the biocompatiblefluid component, and (iii) at least one agent dispersed, suspended, ordissolved within the inner core, wherein the at least one agentcomprises a peptide or protein and has the structureA(-L-)_(m)S_(n) wherein A is a residue of the peptide or protein, m andn are independently integers in the range of 1-4; L is a covalent bondor a linker moiety, and S is a polyoxyethylene ether group having theformula —(OCH₂CH₂)_(p)OR, where p is in the range of 2-12 and R is aC₁-C₄ alkyl group; wherein the inner core is a viscous paste or a gel; afirst polymer layer, impermeable to the passage of the at least oneagent, that covers at least part of but less than 100% of said innercore; and a second polymer layer, permeable to the passage of the atleast one agent, wherein the permeability of the second polymer layer tothe passage of the at least one agent permits the at least one agent todiffuse from the inner core when the drug delivery system is surroundedby a physiological fluid.
 2. The drug delivery system of claim 1,wherein the biocompatible fluid component is polyethylene glycol.
 3. Thedrug delivery system of claim 1, wherein the biocompatible solidcomponent is poly(dl-lactide-co-glycolide).
 4. The drug delivery systemof claim 1, wherein the first polymer layer covers at least about 50% ofthe inner core.
 5. The drug delivery system of claim 1, wherein thefirst polymer layer is formed of a material selected from polyvinylacetate, cross-linked polyvinyl alcohol, cross-linked polyvinylbutyrate, ethylene ethylacrylate copolymer, polyethyl hexylacrylate,polyvinyl chloride, polyvinyl acetals, plasticized ethylene vinylacetatecopolymer, polyvinyl alcohol, ethylene vinylchloride copolymer,polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides,polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinylchloride, plasticized nylon, plasticized soft nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene chlorinatedpolyethylene, poly(1,4-isopropylidene diphenylene carbonate), vinylidenechloride, acrylonitrile copolymer, vinyl-chloride-diethyl fumaratecopolymer, silicone rubbers, medical grade polydimethylsiloxanes,ethylene-propylene rubber, silicone-carbonate copolymers, vinylidenechloride-vinyl chloride copolymer, vinyl chloride-acrylonitrilecopolymer, and vinylidene chloride-acrylonitrile copolymer.
 6. The drugdelivery system of claim 1, wherein the first polymer layer is formed ofa material selected from cross-linked polyvinyl alcohol, plasticizedethylene vinylacetate copolymer, polyvinyl alcohol,polymethylmethacrylate, plasticized nylon, plasticized soft nylon,silicone rubbers, and silicone-carbonate copolymers.
 7. The drugdelivery system of claim 1, wherein the at least one agent has apermeability coefficient in the second layer at least about 1×10⁻⁵ cm/sbut less than about 1×10⁻² cm/s.
 8. The drug delivery system of claim 1,wherein the at least one agent has a release rate from the drug deliverysystem that is limited primarily by the permeability of the at least oneagent in the inner core.
 9. The drug delivery system according to claim1, wherein the system is water-permeable.
 10. A drug delivery device,comprising: the drug delivery system according to claim 1; and apharmaceutically acceptable carrier capable of delivering the at leastone agent to a site within the body.
 11. A method of administering anagent to a patient in need thereof, comprising: providing the drugdelivery system according to claim 1, said system containing aneffective amount of an agent suitable for treating the patient; andadministering the drug delivery system to the patient.
 12. A medicaldevice, comprising the drug delivery system according to claim 1 adaptedto provide a therapeutically effective amount of a drug to a patient inneed thereof.
 13. A method of manufacturing a drug delivery system,comprising: providing an inner core, said inner core comprising (i) abiocompatible fluid component; (ii) a biocompatible solid component,wherein said biocompatible solid component comprises a bioerodiblepolymer, and said biocompatible solid component is dissolved, suspended,or dispersed in the biocompatible fluid component, (iii) at least oneagent dispersed within said inner core, wherein the at least one agentcomprises a peptide or protein and has the structureA(-L-)_(m)S_(n) wherein A is a residue of the peptide or protein, m andn are independently integers in the range of 1-4; L is a covalent bondor a linker moiety, and S is a polyoxyethylene ether group having theformula —(OCH₂CH₂)_(p)OR, where p is in the range of 2-12 and R is aC₁-C₄ alkyl group; wherein the inner core is a viscous paste or a gel;combining said inner core with a first polymer layer that is impermeableto the at least one agent and covers at least part of but less than 100%of said inner core; and adding a second polymer layer that is permeableto the passage of the at least one agent, wherein the permeability ofthe second polymer layer to the passage of the at least one agentpermits the at least one agent to diffuse from the inner core when thedrug delivery system is surrounded by a physiological fluid.
 14. Themethod of claim 13, wherein the inner core and first polymer layer arecombined by co-extrusion.
 15. The method of claim 13, wherein thebiocompatible fluid component is polyethylene glycol.
 16. The method ofclaim 13, wherein the biocompatible solid component ispoly(dl-lactide-co-glycolide).
 17. A method of claim 13, wherein thefirst polymer layer is formed of a material selected from polyvinylacetate, cross-linked polyvinyl alcohol, cross-linked polyvinylbutyrate, ethylene ethylacrylate copolymer, polyethyl hexylacrylate,polyvinyl chloride, polyvinyl acetals, plasticized ethylene vinylacetatecopolymer, polyvinyl alcohol, ethylene vinylchloride copolymer,polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides,polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinylchloride, plasticized nylon, plasticized soft nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene chlorinatedpolyethylene, poly(1,4-isopropylidene diphenylene carbonate), vinylidenechloride, acrylonitrile copolymer, vinyl-chloride-diethyl fumaratecopolymer, silicone rubbers, medical grade polydimethylsiloxanes,ethylene-propylene rubber, silicone-carbonate copolymers, vinylidenechloride-vinyl chloride copolymer, vinyl chloride-acrylonitrilecopolymer, and vinylidene chloride-acrylonitrile copolymer.
 18. A methodof claim 17, wherein the first polymer layer is formed of a materialselected from cross-linked polyvinyl alcohol, plasticized ethylenevinylacetate copolymer, polyvinyl alcohol, polymethylmethacrylate,plasticized nylon, plasticized soft nylon, silicone rubbers, andsilicone-carbonate copolymers.
 19. The drug delivery system of claim 1,wherein the first polymer layer comprises a synthetic polymer.
 20. Thedrug delivery system of claim 1, wherein the system delivers the atleast one agent over a period of at least 1 week when implanted in thepatient.
 21. The drug delivery system of claim 1, wherein the systemdelivers the at least one agent over a period of at least 2 days whenimplanted in a patient.
 22. The drug delivery system of claim 1, whereinthe biocompatible solid component is more soluble in the biocompatiblefluid component than in physiological fluid.
 23. The drug deliverysystem of claim 1, wherein the second polymer layer covers at least partof the first polymer layer.
 24. The method of claim 11, whereinadministering comprises injecting the system into the patient.
 25. Thedrug delivery system of claim 1, wherein the inner core is a viscouspaste.
 26. The drug delivery system of claim 1, wherein the inner coreis a gel.
 27. The method of claim 13, wherein the inner core is aviscous paste.
 28. The method of claim 13, wherein the inner core is agel.